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A method based on solid-phase extraction (SPE) coupled to high-performance liquid chromatography (HPLC) with positive ion electrospray ionization tandem mass spectrometry (ESI-MS/MS) detection was developed for the simultaneous determination of lamivudine (3TC) and zidovudine (AZT) in human serum, using didanosine (ddI) as internal standard. The acquisition was performed in multiple reaction monitoring (MRM) mode, monitoring the transitions m/z 230.0 --> 111.8 for 3TC, m/z 268.1 --> 126.8 for AZT, and m/z 237.2 --> 136.8 for ddI. The limits of detection and quantitation were 3 and 10 ng/mL for 3TC, and 5 and 15 ng/mL for AZT. The method was linear in the studied ranges (10-1500 ng/mL for 3TC and 15-3000 ng/mL for AZT), with r(2) > 0.99 for each drug, and the run time was 4 min. The intra-assay precisions (%) were in the ranges 1.9-8.7 (3TC) and 2.2-8.9 (AZT), the inter-assay precisions were in the ranges 2.6-9.0 (3TC) and 4.2-8.1 (AZT), and the intra- and inter-assay accuracies were >97% for both drugs. The absolute recoveries were 95-99% for 3TC (45, 600 and 1200 ng/mL) and 104-112% for AZT (45, 1000 and 2400 ng/mL). The analytical method was applied to a bioequivalence study in which 24 healthy adult volunteers received single oral doses of the reference formulation and two test combined AZT/3TC tablets, in an open, three-period, balanced, randomized, crossover protocol. Based on the 90% confidence interval of the individual ratios (test formulation/reference formulation) for C(max) (peak serum concentration) and AUC(0-inf) (extrapolated area under the serum concentration vs. time curve from time zero to infinity), it was concluded that the two test formulations are bioequivalent to the reference formulation with respect to the rate and extent of absorption of both 3TC and AZT.

A lopinavir-ritonavir (LPV/r)-based regimen is recommended during pregnancy to reduce the risk of HIV mother-to-child transmission, but the appropriate dose is controversial. We compared the pharmacokinetics of standard and increased LPV/r doses during pregnancy. This randomized, open-label prospective study enrolled 60 pregnant women between gestational weeks 14 and 30. The participants received either the standard dose (400/100 mg twice a day [BID]) or increased dose (600/150 mg BID) of LPV/r tablets during pregnancy and the standard dose for 6 weeks after childbirth. Pharmacokinetics analysis was performed using a high-performance liquid chromatography-tandem mass spectrometry method. Adherent participants who received the standard dose presented minimum LPV concentrations of 4.4, 4.3, and 6.1 g/ml in the second and third trimesters and postpartum, respectively. The increased-dose group exhibited values of 7.9, 6.9, and 9.2 g/ml at the same three time points. Although LPV exposure was significantly higher in the increased-dose group, the standard dose produced therapeutic levels of LPV against wild-type virus in all adherent participants, except one patient in the third trimester; 50%, 37.5%, and 25%, and 0%, 15%, and 0% of the participants in the standard-and increased-dose groups failed to achieve therapeutic levels against resistant viruses during the second and third trimesters and after childbirth, respectively. After 12 weeks of treatment and after childbirth, all adherent participants achieved undetectable HIV viral loads, and their babies (49/54) were uninfected. No serious drug-related adverse events were observed. We conclude that the standard dose is appropriate for use during pregnancy and that an increased dose may be necessary for women harboring resistant HIV. (This study has been registered at ClinicalTrials.gov under registration no. NCT00605098.)

The ABCB1 1236C>T, 2667G>T/A and 3435C>T genotypes and haplotypes are not predictors of lopinavir and ritonavir concentrations in blood plasma, semen or saliva of HIV-infected men under stable HAART treatment. The concentrations of lopinavir and ritonavir in saliva are not reliable predictors of the concentration of these drugs in semen.

Therapeutic monitoring of the antibiotic vancomycin is important to achieve specific plasma concentration and prevent toxic effects. Several assays have been described for vancomycin determination in clinical practice, but high-performance liquid chromatography is still considered the gold standard for the quantification of vancomycin. In this study, we developed a new and rapid high-performance liquid chromatography method requiring 50 μL of plasma for the quantification of vancomycin. Acetonitrile was used for processing plasma by protein precipitation (1:2.5). Isocratic chromatographic analysis was carried out on a C18 silica-based (2.7 μm) column with the mobile phase containing 20 mM ammonium acetate/formic acid buffer (pH 4.0):methanol 88:12 (v/v). A diode array detector was used for UV detection at 240 nm. This method was validated according to the Brazilian Health Surveillance Agency legislation and International Conference on Harmonization guidelines. The measurement range was 1-100 μg/mL, analysis time was 8 min, and intermediate precision was <12%, supporting the present method as a fast, simple, and effective alternative for therapeutic monitoring of vancomycin.

A method based on solid-phase extraction (SPE) coupled to high-performance liquid chromatography (HPLC) with positive ion electrospray ionization tandem mass spectrometry (ESI-MS/MS) detection was developed for the determination of stavudine in human serum, using didanosine as internal standard. The acquisition was performed in multiple reaction monitoring (MRM) mode. The method was linear over the studied range (10-2000 ng/mL), with r(2) > 0.99, and the run time was 4 min. The intra- and inter-assay precisions (%) were in the ranges 0.1-13.6 and 2.6-9.9, respectively, and the intra- and inter-assay accuracies were >92%. The absolute recoveries were approximately 100% (10 ng/mL), 98% (30 ng/mL), 105% (750 ng/mL) and 105% (1500 ng/mL). The limits of detection and quantitation were 4 and 10 ng/mL, respectively. The analytical method was applied to a bioequivalence study, in which 24 healthy adult volunteers (12 men) received single oral doses (40 mg) of reference and two test stavudine formulations, in an open, three-period, randomized, crossover protocol. The 90% confidence interval of the individual ratios (test formulation/reference formulation) for C(max) (peak serum concentration), AUC(0-10) and AUC(0-inf) (areas under the serum concentration vs. time curve from time zero to 10 h and to infinity, respectively), were in the range 80-125%, which supports the conclusion that the two test formulations are bioequivalent to the reference formulation with respect to the rate and extent of stavudine absorption.

Vancomycin (VAN) is the gold standard therapy for Methicillin-resistant Staphylococcus aureus (MRSA) infections such as bacteremia and endocarditis. However, VAN suboptimal dosing for serious infections caused by S. aureus isolates that have elevated minimum inhibitory concentration (MIC), could be associated with poor outcome. Better understanding of VAN pharmacokinetics and pharmacodynamics (PK/PD) has led to the creation of new recommendations with optimized dosing regimens for the treatment of MRSA infections. For severe infectious, such as pneumonia and endocarditis, a VAN serum trough concentration of 15-20 mg/L at the steady state should be targeted. The aim of this study was to show how a nomogram with updated VAN dosing was devised and how it was implemented in the electronic prescribing (e-prescribing) system of a teaching hospital. VAN loading dose and maintenance doses were calculated from a pharmacokinetic equation using basic parameters: weight, estimated creatinine clearance, as well as peak and trough serum concentrations. The implementation of the VAN dosing nomogram in the hospital e-prescribing system definitively changed the long-standing medical prescription fallacy of "same dose fits all". Finally, this computer-based electronic program has allowed a wide-ranging intervention and should be recognized as a powerful tool for implementation in antimicrobial stewardship programs.Uniterms: Vancomycin/prescribing. Methicillin/use. Staphylococcus aureus/methicillin-resistant. Electronic prescribing system/application in hospital. Antibiotics/rational use. Antimicrobials/rational use. Vancomicina (VAN) é utilizada como primeira escolha na terapia de infecções causadas porStaphylococcus aureus resistentes à meticilina (MRSA), como bacteremia e endocardite. Entretanto, o aumento na concentração inibitória mínima (CIM) de isolados de S. aureus e doses subterapêuticas de VAN podem estar associados à falha terapêutica. Para o melhor entendimento sobre o perfil farmacocinético e farmacodinâmico (PK/PD) da VAN foram elaboradas novas recomendações para terapia de infecções causadas por MRSA. Para terapia de infecções graves, como pneumonia e endocardite, a concentração sérica do vale de VAN de 15-20 mg/L no estado de equilíbrio dinâmico deve ser o alvo. O objetivo do estudo foi desenvolver um nomograma com doses atualizadas de VAN e demonstrar como ele foi implementado no sistema de prescrição eletrônica em um Hospital Universitário. As doses de ataque e manutenção foram calculadas a partir de equações farmacocinéticas, utilizando parâmetros fundamentais: peso, depuração de creatinina, concentrações séricas do pico e do vale. A implementação de um nomograma de doses de VAN em um sistema de prescrição eletrônica modificou definitivamente o inadequado hábito de que "a mesma dose cabe em todos". Finalmente, esta abrangente ferramenta tecnológica deve ser considerada como uma robusta estratégia num programa de uso racional de antibióticos.Unitermos: Vancomicina/prescrição. Meticilina/uso. Staphylococcus aureus...

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